Despite the advances in the neurophysiological study of sleep, the primary mechanisms and propagating pathways exerting control over state-dependent neuronal activity are largely unknown. In fact, alterations in the activity of single cells throughout the CNS coordinate precisely with awake and sleep states. This proposal represents an attempt to elucidate the systems responsible for dissemination of state-induced influences throughout the brain. The initial site of investigation is the thalamus because a great deal is known about its intrinsic and extrinsic circuitry, and evidence is abundant indicating that these cells are the recipients of state-related information. We will attempt to identify the neurotransmitter-receptor interactions subserving state regulation of thalamic neuronal activity in waking, REM sleep, and slow wave sleep. The main hypotheses to be tested are: 1) cholinergic afferents from brain stem facilitate relay cell activity and inhibit activity in the thalamic reticular nucleus (TRN) in waking and REM sleep; 2) glutaminergic afferents from cortex facilitate both relay and TRN cell activity in waking and REM sleep, and 3) GABAergic afferents from TRN and/or interneurons inhibit relay cell activity in slow wave sleep. Pharmacological agents directed at specific receptors will be microiontophoretically applied to electrophysiologically-identified thalamic cells, which are monitored extracellularly. Responses are recorded in unanesthetized rats spontaneously cycling through waking and sleep states. Putative neurotransmitter substances mediating the control of state-dependent activity will be indicated by the effects of specific agonists and antagonists. The results of these experiments will yield an understanding at the recipient cellular level of the operations of the neurophysiological systems that propagate sleep-state regulation messages. Future investigations will be directed at the next proximal cell populations found to be responsible for transmission of the state-associated information to the currently studied thalamic sites. This strategy, in step-wise fashion, seeks to map the neural network responsible for propagating state-dependent cell activity throughout the brain. Data about these control mechanisms are essential to understanding the neural sequences that subserve sleep behavior and the physiological phenomenology represented in sleep and waking.